The present invention relates to novel aminomethylphenoxymethyl/benzisoxazole substituted azabicyclic compounds, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use. The compounds of the present invention include selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1D receptors. They are useful in treating or preventing migraine, depression and other disorders for which a 5-HT1 agonist or antagonist is indicated.
European Patent Publication 434,561, published on Jun. 26, 1991, refers to 7-alkyl, alkoxy, and hydroxy substituted-1-(4-substituted-1-piperazinyl)-naphthalenes. The compounds are referred to as 5-HT1 agonists and antagonists useful for the treatment of migraine, depression, anxiety, schizophrenia, stress and pain.
European Patent Publication 343,050, published on Nov. 23, 1989, refers to 7-unsubstituted, halogenated, and methoxy substituted-1-(4-substituted-piper-azinyl)-naphthalenes as useful 5-HT1A ligand therapeutics.
PCT publication WO 94/21619, published Sep. 29, 1994, refers to naphthalene derivatives as 5-HT1 agonists and antagonists.
PCT publication WO 96/00720, published Jan. 11, 1996, refers to naphthyl ethers as useful 5-HT1 agonists and antagonists.
European Patent Publication 701,819, published Mar. 20, 1996, refers to the use of 5-HT1 agonists and antagonists in combination with a 5-HT re-uptake inhibitor.
Glennon et al., refers to 7-methoxy-1-(1-piperazinyl)-naphthalene as a useful 5-HT1 ligand in their article xe2x80x9c5-HT1D Serotonin Receptorsxe2x80x9d, Clinical Drug Res. Dev., 22, 25-36 (1991).
Glennon""s article xe2x80x9cSerotonin Receptors: Clinical Implicationsxe2x80x9d, Neurscience and Behavioral Reviews, 14, 35-47 (1990), refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer""s disease, Parkinson""s disease and Huntington""s disease.
World Patent Application WO 95/31988, published Nov. 30, 1995, refers to the use of a 5-HT1D antagonist in combination with a 5-HT1A antagonist to treat CNS disorders such as depression, generalized anxiety, panic disorder, agoraphobia, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, memory disorders, anorexia nervosa and bulimia nervosa, Parkinson""s disease, tardive dyskinesias, endocrine disorders such as hyperprolactinaemia, vasospasm (particularly in the cerebral vasculature) and hypertension, disorders of the gastrointestinal tract where changes in motility and secretion are involved, as well as sexual dysfunction.
G. Maura et al., J. Neurochem, 66 (1), 203-209 (1996), have stated that administration of agonists selective for 5-HT1A receptors or for both 5-HT1A and 5-HT1D receptors might represent a great improvement in the treatment of human cerebellar ataxias, a muflifaceted syndrome for which no established therapy is available.
European Patent Publication 666,261, published Aug. 9, 1995 refers to thiazine and thiomorpholine derivatives which are claimed to be useful for the treatment of cataracts.
The present invention relates to compounds of the formula 
wherein
R3, R4, and Z are selected, independently, from hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), (C1-C4) alkyl optionally substituted with from one to three fluorine atoms, (C1-C4)alkoxy optionally substituted with from one to three fluorine atoms, and (C1-C4)alkoxy-(C1-C4)alkyl wherein each of the alkyl moieties may optionally be substituted with from one to three fluorine atoms;
W is xe2x80x94CH2xe2x80x94Oxe2x80x94(C1-C6) alkyl wherein the alkyl moiety can be straight or branched;
or W is xe2x80x94CH2NR1R2 wherein R1 and R2 are independently selected from hydrogen and straight or branched (C1-C6)alkyl;
or R1 and R2, together with the nitrogen to which they are attached, form a saturated four membered monocyclic ring or a saturated or unsaturated nonaromatic five to seven membered monocyclic ring or a saturated or unsaturated nonaromatic seven to ten membered bicyclic ring which may optionally contain one or two heteroatoms in addition to the nitrogen of NR1R2, wherein said heteroatoms are independently selected from oxygen, nitrogen and sulfur, and wherein from one to three of the ring carbon atoms, or one of the ring nitrogen atoms, may optionally and independently be substituted with straight or branched (C1-C4) alkyl, straight or branched (C1-CG) alkoxy, straight or branched (C1-C3) alkyl(C3-C7) cycloalkyl, hydroxy, amino, cyano, halo, aryl-(straight or branched (C1-C3) alkyl) or heteroaryl-(straight or branched (C1-C3) alkyl), wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from oxazolyl, isoxazoyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl, pyrazinyl, cinnolinyl, pyridinyl and pyrimidinyl;
with the proviso that in any ring formed by NR1R2: (a) there can be -no more than one ring oxygen atom; (b) there can be no hydroxy, alkoxy, alkoxyalkyl, cyano, amino or alkylamino moiety bonded directly to any ring nitrogen atom; and (c) no ring carbon that is double bonded to another ring carbon and not part of an aromatic ring system can be bonded to a ring oxygen atom or ring nitrogen atom.
Examples of preferred compounds of the formula I are those having the absolute stereochemical configuration defined as 7R, 9aS -trans or as 7S, 9aS -cis.
Examples of specific embodiments of this invention are the following compounds of the formula I and their pharmaceutically acceptable salts:
(7R,9as)-trans-1-{3-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydropyrido[1,2-a]pyrazin-7-ylmethoxy]-benzyl}-azetidin-3-ol;
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-y)-7-(3-morpholin-4-ylmethylphenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9as)-cis-1-(3-{1-[2-(Benzo[d]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperidin-3-ylmethoxy}-benzyl)-azetidin-3-ol;
(7R,9aS)-trans-2-(4-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine;
(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]pyrrolidine-3,4-diol;
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydropyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-methyl-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-methoxy-5-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloro-3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-7-(3-azetidin-1-ylmethyl-phenoxymethyl)-2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclopropylmethyl-amine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclopropyl-amine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyridol[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(4-ethyl-piperazin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-cyclohexyl-amine;
(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyridol[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidin-3-ol;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-[pyrrolidin-1-ylmethyl)-phenoxymethyl-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-[3-(2,5-dimethyl-pyrrolidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyridol[1,2-a]pyrazine;
(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidine-3,4-diol;
(7S,9aS)-cis-1-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-pyrrolidin-3-ol;
(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzyl]-isobutyl-amine;
(7S,9aS)-cis-Benzo[d]isoxazol-3-yl-methyl-{2-[2-methyl-5-(2-morpholin-4-methyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-amine;
(7S ,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyridol[1,2-a]pyrazine;
(7S ,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-pyrrolidin-1-ylmethyl -phenoxymethyl)-octahydro-pyridol[1,2-a]pyrazine;
(7R,9aS)]-trans-2-(7-Fluoro-benzo[d]isoxazol-3-yl)-7-3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-trans-2-(6Fluoro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-trans-2-(6,7-Difluoro-benzodisoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-trans-3-(3-[2-(5-Fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzyl)-3-aza-bicyclo[3,2,2]nonane and;
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-Cis-octahydro-isoindol-2-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a]pyrazine.
Other specific embodiments of this invention are the following compounds of the formula I and their pharmaceutically acceptable salts:
(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-trans-2-(5-Chloro-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-trans-2-(5-Methyl-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-trans-2-Benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-cis-2-Benzo[d]isoxazol-3-yl)-7-(2-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(2-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(4-morpholin-4-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-trans-2-(2-Methoxy-benzo[d]isoxazol-3-yl)-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-(5-Methoxy-benzo[d]isoxazol-3yl-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-(3-(2-methoxymethyl-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrdo[1,2-a]pyrazine;
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(2-methoxymethyl-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7R,9aS)-tans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(2-methoxymethyl-piperidin1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine; and
(7R,9aS)-trans-2-(5-Fluoro-benzo[d]isoxazol-3-yl)-7-[3-(3-methoxymethyl-piperidin-1-ylmethyl)-phenoxymethyl]-octahydro-pyrido[1,2-a].
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating such disorder or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those enumerated in the preceding paragraph.
The present invention also relates to a method for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (, agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer, (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
The present invention also relates to a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal in need of such treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive dedine (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising a serotonin 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising a serotonin 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating a disorder or condition selected from hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders) in a mammal, preferably a human, comprising administering to a mammal requiring such treatment a serotoninn 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound of the formula I or a pharmaceutically acceptable salt thereof.
The present invention also relates to a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal requiring such treatment a serotonin 1A receptor antagonizing or agonizing effective amount, or a serotonin 1D receptor antagonizing effective amount, of a compound of the formula I or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical composition for treating a condition or disorder that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising:
a) a pharmaceutically acceptable carrier;
b) a compound of the formula I or a pharmaceutically acceptable salt thereof; and
c) a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof;
wherein the amount of the active compounds (i.e., the compound of formula I and the 5-HT re-uptake inhibitor) are such that the combination is effective in treating such disorder or condition.
The present invention also relates to a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising administering to a mammal requiring such treatment:
a) a compound of the formula I, defined above, or a pharmaceutically acceptable salt thereof; and
b) a 5-HT re-uptake inhibitor, preferably sertraline, or a pharmaceutically acceptable salt thereof;
wherein the amounts of the active compounds (i.e., the compound of formula I and the 5-HT re-uptake inhibitor) are such that the combination is effective in treating such disorder or condition.
The present invention also relates to a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising administering to said mammal requiring such treatment:
a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable salt thereof; and
b) a 5-HT1D antagonist of formula I or a pharmaceutically acceptable salt thereof:
wherein the amounts of each active compound (i.e., the 5-HT1A agonist or antagonist and the 5-HT1D antagonist) are such that the combination is effective in treating such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, preferably a human, comprising:
a) a 5-HT1A agonist or antagonist or a pharmaceutically acceptable salt thereof; and
b) a 5-HT1D antagonist of formula I or a pharmaceutically acceptable salt thereof;
wherein the amounts of each active compound (i.e., the 5-HT1A agonist or antagonist and the 5-HT1D antagonist) are such that the combination is effective in treating such disorder or condition.
This invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. Examples of pharmaceutically acceptable acid addition salts of the compounds of formula I are the salts of hydrochloric acid, p-toluenesulfonic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, malate, di-p-toluoyl tartaric acid, and mandelic acid.
Unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d, as used herein, includes fluoro, chloro, bromo and iodo.
Unless otherwise indicated, the term xe2x80x9calkylxe2x80x9d, as used herein, may be straight, branched or cyclic, and may include straight and cyclic moieties as well as branched and cyclic moieties.
The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such condition or disorder. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
The compounds of formula I may have optical centers and therefore may occur in different enantiomeric configurations. The invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of formula I, as well as racemic and other mixtures thereof.
The present invention also relates to all radiolabelled forms of the compounds of the formula I. Preferred radiolabelled compounds of formula I are those wherein the radiolabels are selected from as 3H, 11C, 14C, 18F, 123I and 125I. Such radiolabelled compounds are useful as research and diagnostic tools in metabolism pharmacokinetics studies and in binding assays in both animals and man.
xe2x80x9cModulating serotonergic neurotransmission,xe2x80x9d as used herein, refers to increasing or improving, or decreasing or retarding the neuronal process whereby serotonin is released by a pre-synaptic cell upon excitation and crosses the synapse to stimulate or inhibit the post-synaptic cell.
xe2x80x9cChemical dependency,xe2x80x9d as used herein, means an abnormal craving or desire for, or an addiction to a drug. Such drugs are generally administered to the affected individual by any of a variety of means of administration, including oral, parenteral, nasal or by inhalation. Examples of chemical dependencies treatable by the methods of the present invention are dependencies on alcohol, nicotine, cocaine, heroin, phenolbartitol, and benzodiazepines (e.g., Valium (trademark)). xe2x80x9cTreating a chemical dependency,xe2x80x9d as used herein, means reducing or alleviating such dependency.
Sertraline, (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, as used herein has the chemical formula C17H17NCl2 and the following structural formula 
Its synthesis is described in U.S. Pat. No. 4,536,518. assigned to Pfizer Inc. Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation.
This invention also relates to compounds of the formula 
wherein the stereochemistry is either (7R, 9aS)-trans or (7S, 9aS)-cis;
T is selected from HOCH2xe2x80x94, HC(xe2x95x90O)xe2x80x94, H3CO2SOCH2xe2x80x94, xe2x80x94CH2NR1R2, straight or branched (C1-C6)alkoxy, and 
wherein
Z is defined as in the definition of compounds of the formula I; and
V is selected from hydrogen, t-butoxycarbonyl, groups having the formula 
wherein R3 and R4 are selected, independently, from hydrogen, chloro, fluoro, methyl and methoxy, and groups having the formula 
wherein R3 and R4 are defined as above and the oximino moiety may be syn, anti, or a mixture of syn and anti isomers.
Such compounds are useful in the synthesis of compounds of the formula I.
Examples of specific compounds of the formula G are the following:
7R,9aS)-trans-7-(3-methoxycarbonylphenoxymethyl)-octahydro-pyrido-1,2-a]pyrazine-2-carboxylic acid tert-butyl ester;
(7R,9aS)-trans-7-(3-hydroxymethylphenoxymethyl)-octahydro-pyrido-[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester;
(7R,9aS)-trans-7-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester;
(7R,9aS)-trans-3-(3-pyrrolidin-1-ylmethyl-phenoxymethyl)-octahydro-quinazolizine dihydrochloride and mineral bis-salts thereof;
(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido-1,2-a]pyrazin-7-yl]-methanol;
(7S,9aS)-trans-3-[2-(fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-benzoic acid methyl ester;
(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanol;
(7R,9aS)-trans-{3-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy]-phenyl}-methanol methane sulfonate;
(7S,9aS)-cis-7-(3-methoxycarbonyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester;
(7S,9aS)-cis-{2-[5-(3-hydroxymethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]ethyl}-methyl-carbamic acid tert-butyl ester;
(7S,9aS)-cis-3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzoic acid methyl ester;
(7S,9aS)-cis-[3-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-phenyl]-methanol;
(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzoic acid methyl ester;
(7S,9aS)-cis-[4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)phenyl]-methanol;
(7S,9aS)-cis-2-Benzo[d]isoxazol-3-yl-7-(4-chloromethyl-phenoxymethyl)-octahydro-pyrido[1,2-a]pyrazine;
(7S,9aS)-cis-2-{1-[2-(Benzo[d]isoxazol-3-yl-methyl-amino)-ethyl]-6-methyl-piperidin-3-ylmethoxy}-benzonitrile;
(7S,9aS-{2-[5-(2-Aminomethyl-phenoxymethyl)-2-methyl-piperidin-1-yl]-ethyl}-benzo[d]isoxazol-3-yl-methyl-amine;
(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-benzonitrile;
(7S,9aS)-cis-4-(2-Benzo[d]isoxazol-3-yl-octahydro-pyrido-1,2-a]pyrazin-7-ylmethoxy)-benzylamine;
(7S,9aS)-cis-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyrido[1,2-a]pyrazin-7-yl]-methanol;
(7S,9aS)-cis-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazine-7-carboxaldehyde;
(7R,9aS)-trans-2-(5-fluoro-benzo[d]isoxazol-3-y)-octahydro-pyridol[1,2-a]pyrazin-7-carboxaldehyde;
(7R,9aS)-trans-[2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl]-methanol and; and (7R,9aS)-trans-methanesulfonic acid-2-(5-fluoro-benzo[d]isoxazol-3-yl)-octahydro-pyridol[1,2-a]pyrazin-7-yl-ester.
Compounds of the formula I may be prepared according to the following reaction schemes and discussion. Unless otherwise indicated, W, Z, T, V, R1, R2, R3 and R4 and structural formulas I and G in the reaction schemes and discussion that follow are as defined above. 
Schemes 1-7 illustrate methods of preparing compounds of the formula I.
Scheme 1 illustrates a method of preparing compounds of the formula I having the (7R, 9aS)-trans stereochemistry. Referring to Scheme 1, the, compound formula II is combined with the compound of formula III, under Mitsunobu coupling conditions, in the presence of triphenylphosphine and a compound of the formula RO2CNxe2x95x90NCO2R (IV), wherein R is methyl or ethyl, to form the compound of formula V. (See O. Mitsunobu, Synthesis, 1 (1981)). Suitable solvents for this reaction include tetrahydrofuran (THF), other ethers and halocarbon solvents, with THF being preferred. This reaction is generally conducted at a temperature from about room temperature to about 65xc2x0 C., for about 1 to about 24 hours. It is preferably conducted at about 50xc2x0 C. for about 4 to 18 hours.
Reduction of the compound of formula V yields the compound of formula VI. This reduction can be accomplished using lithium aluminum hydride as the reducing agent, in a solvent selected from, diethyl ether and other dialkyl ethers, preferably diethyl ether, at a temperature from about xe2x88x925xc2x0 C. to about room temperature, for about 0.5 to about 18 hours.
The compound of formula VI can then be converted into the compound of formula VII by reacting it with methanesulfonyl chloride, in the presence of a tertiary amine base such as triethylamine (TEA), in methylene chloride or another halocarbon solvent, at a temperature from about xe2x88x925xc2x0 C. to about room temperature, for a period of about 10 minutes to about 2 hours.
Reaction of the resulting compound of formula VII with a compound of the formula HNR1R2, wherein R1 and R2, together with the nitrogen to which they are attached, may form a ring, as depicted in Scheme 1, yields the corresponding compound having formula VIII. Typically, this reaction is carried out in THF, N,N-dimethylformamide (DMF) or acetonitrile, or a mixture of two or more or the foregoing solvents, at a temperature from about room temperature to about 100xc2x0 C., for a period from 1 to about 18 hours. The compound of formula VIII is then deprotected to form the hydrochloric acid addition salt of the corresponding compound of formula IX. This can be accomplished using anhydrous hydrochloric acid (HCl) in diethyl ether, another dialkyl ether or a halocarbon solvent at about room temperature. This reaction can also be carried out without a solvent using trifluoroacetic acid, in which case the bitrifluoroacetic acid addition salt is formed. This reaction is generally run from about 2 to about 18 hours.
The desired corresponding compound of formula I-a can be formed by reacting the compound of formula IX from the foregoing reaction with the appropriate compound of formula X, wherein R3 and R4 are as defined above in the definition of compounds of the formula I, and 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU). This reaction is typically conducted in pyridine, at a temperature from about 50xc2x0 C. to about 110xc2x0 C., for a period of about 1 to about 48 hours.
Scheme 2 illustrates an alternate method of making compounds of the formula I-a. Referring to Scheme 2, the starting material of formula II is deprotected using the conditions and reactants described above for the preparation of compounds of the formula IX, to form the dihydrochloric acid or ditrifluoroacetic acid addition salt of the resulting compound of formula XI. Reaction of the resulting compound of formula XI, in the presence of an organic base such as DBU, with the compound of formula XI yields the corresponding compound of formula XII.
The compound of formula XII produced in the foregoing reaction is then reacted with 3-hydroxybenzoic acid methyl ester (III), in the presence of triphenylphosphine and a compound of the formula RO2CNxe2x95x90NCO2R (IV), wherein R is methyl or ethyl, using the reaction conditions described above for the preparation of compounds of the formula V, to form the corresponding compound of formula XII, which is then reduced, to form the corresponding compound of formula XIV. The reduction can be accomplished using lithium aluminum hydride as the reducing agent, in a solvent selected form THF, diethyl ether and other dialkylethers, preferably THF, at a temperature from about xe2x88x925xc2x0 C. to about room temperature, for about 0.5 to about 18 hours.
The compound of XIV is then converted into the corresponding compound of formula XV in a manner analogous to the conversion of the compound of formula VI into that of formula VII, which is illustrated in Scheme 1 and described above. The desired final product of formula I-a can then be obtained-from the corresponding compound of the formula XV and the appropriate compound of formula HNR1R2, wherein R1 and R2, together with the nitrogen to which the are attached, may form a ring, as depicted in Scheme 2, using the procedures described above for converting the compound of formula VII into a compound of the formula VIII.
Scheme 3 Illustrates the preparation of compounds of the formula I having the (7S, 9aS)-cis stereochemistry. These compounds are defined in Scheme 3 and hereinafter as compounds of the formula I-b. The reactions illustrated in this scheme are carried out using reagents and conditions analogous to those described above in Scheme 1 for converting the compound of formula II into a compound of the formula I-a.
Scheme 4 illustrates alternate methods of making compounds of the formula I-b. As illustrated in Scheme 4, compounds of the formula I-b wherein the aminomethyl containing sidechain is attached to the phenoxy group at the 3xe2x80x2 position can be made using a procedure analogous to that of Scheme 2. The analogous compounds wherein the aminomethyl sidechain is attached to the phenoxy group at the 4xe2x80x2 position proceed through a different intermediate. Specifically, such compounds can be prepared by reacting the corresponding compound of the formula XIVA, wherein the hydroxymethyl group is at the 4xe2x80x2 position, with methanesulfonyl chloride, under the same reaction conditions described above for the formation of the compound of formula VII in Scheme 1, to form the corresponding compound having the formula XVAxe2x80x2. This compound can then be converted into the corresponding compound having the formula I-bxe2x80x2 using a procedure analogous to that described above for the formation of compounds of the formula I-a from the corresponding compounds of formula XV.
Schemes 5 and 5a illustrate a method for preparing compounds of the formula I wherein W is CH2NR1R2. The series of reactions illustrated in Scheme 5 for converting the starting materials of the formula XIIA into those of the formula XIX is analogous to the transformation of the compound of formula XIIA into a compound of the formula XIVA in Scheme 4, with the exception that in the first step of this series, i.e., the reaction that adds the phenoxy substituent, the substituted phenolic reactant is a cyano substituted phenol rather than a hydroxy substituted benzoic acid methyl ester.
The compound of formula XIX can be converted into the desired final product of formula I-c by reacting it with a compound of the formula Xxe2x80x2xe2x80x94R1xe2x80x94R2xe2x80x94Xxe2x80x2, wherein Xxe2x80x2 is bromo, chloro or methanesulfonate and the dashed line represents the portion of the ring structure of the final product connecting R1 and R2, in the presence of a base such as sodium carbonate or an organic base such as DBU, or with compounds of the formulas R1Xxe2x80x2 and R2Xxe2x80x2, sequentially. The reaction with Xxe2x80x2xe2x80x94R1xe2x80x94R2xe2x80x94Xxe2x80x2 (or the sequential reactions with R1Xxe2x80x2 and R2Xxe2x80x2) is generally carried out in a solvent such as N,N-dimethylformamide (DMF), THF or methylene chloride, at a temperature from about room temperature to about 100xc2x0 C., preferably from about 40xc2x0 C. to about 100xc2x0 C., for a period of about 1 to 48 hours. The reactions depicted in Scheme 5a can be carried out in an analogous fashion to those of Scheme 5.
Scheme 6 refers to an alternate method of preparing compounds of a formula I having the same stereochemistry at positions 7 and 9a as compounds of the formula I-a, and wherein the aminomethyl sidechain on the phenoxy group can be attached at any position (i.e., ortha, meta or para) of that group. These compounds are referred to in Scheme 6 and hereinafter as compounds of the formula I-d. Referring to Scheme 6, the dihydrochloride salt of the appropriate compound of the formula IX is reacted with syn, anti, or a mixture of the syn and anti isomers of a compound of the formula 
(i.e., the appropriately substituted benzohydroximinoyl chloride), in the presence of a base such as DBU, to form the corresponding compound of formula XX. Suitable solvents for this reaction include chlorohydrocarbons such as chloroform and methylene chloride. Suitable reaction temperatures range from about xe2x88x9278xc2x0 C. to about 50xc2x0 C. This reaction is preferably conducted at a temperature from about 20xc2x0 C. to about 40xc2x0 C., for a period of about 0.5 to about 24 hours.
The resulting compound of formula XX can then be converted into the desired final product of formula I-d by reacting it with a strong nucleophilic organic base (e.g., n-butyl lithium) or sodium hydride. This reaction is typically conducted in a solvent such as toluene, DMF or THF, at a temperature from about room temperature to about 110xc2x0 C. for about 1 to 48 hours. Preferably, the solvent is a mixture of toluene and THF and the reaction is carried out at a temperature from about 80xc2x0 C. to about 100xc2x0 C.
Scheme 7 illustrates an alternate method that can be used to form compounds of the formula I-a and the analogous compounds wherein the aminomethyl sidechain is attached to the phenoxy group at the ortho, meta or para positions. Such compounds are referred to in Scheme 7 and hereinafter as xe2x80x9ccompounds of the formula I-dxe2x80x2xe2x80x9d. Referring to Scheme 7, a compound of the formula XIIA is oxidized to form the corresponding (7S,9aS)-cis aldehyde of formula XXIA by dissolving it in dichloromethane containing an excess of N,N-diisopropylethylamine, (in molar equivalents, with respect to the substrate of formula (XIIA)), and treating it with a slurry of pyridine-sulfur trioxide complex in dimethylsulfoxide (DMSO) at an initial temperature below 10xc2x0 C. The reaction mixture is then stirred at about ambient temperature for about 18 hours. The resulting compound of formula XXIA is then epimerized at the C-7 carbon to form the corresponding (7R, 9aS)-trans aldehyde of formula XXI by stirring a methanol solution of the compound of formula XXIA it with solid potassium carbonate at about ambient temperature for about 18 hours.
Reduction of the aldehyde of formula XXI yeilds the corresponding alcohol of formula XII. This reduction can be accomplished by treatment with sodium borohydride in methanol for about 18 hours at about ambient temperature.
The compound of formula XII is reacted with methanesulfonyl chloride, in the presence of a base such as DBU, in methylene chloride, at a temperature from about xe2x88x925xc2x0 C. to about room temperature, for about 10 minutes to about 2 hours. The resulting compound of formula XXI is then reacted with sodium phenolate, wherein the phenyl moiety is substituted with a group of the formula CH2NR1R2 wherein R1 and R2, together with the nitrogen to which they are attached, may form a ring, as described above, to form the desired final product of formula I-dxe2x80x2. Examples of solvents in which this reaction can be conducted are DMF and N-methylpyrrolidinone (NMP). The preferred solvent is NMP. The reaction temperature can range from about 20xc2x0 C. to about 100xc2x0 C., and is preferably between about 70xc2x0 C. and about 100xc2x0 C. Generally, the reaction is run for a period for about 1 to 24 hours. As illustrated in Scheme 7, the resulting compound of formula I-dxe2x80x2 can be converted into the corresponding dihydrochloride salt using methods well known to those of skill in the art. For example, such compound can be treated with 12N hydrochloric acid in acetone, or with anhydrous hydrochloric acid in a mixture of diethyl ether and ethyl acetate or dichloromethane.
All of the above schemes and corresponding discussions with the exception of Schemes 5 and 5a, the moieties represented as xe2x80x94CH2NR1R2 and 
are interchangeable. Also, the same reactions apply to the formation of compounds of the formula I wherein W is alkoxy rather than xe2x80x94CH2NR1R2, in which case the reactant xe2x80x94NHR1R2 is replaced by M+Oxe2x88x92xe2x80x94(C1-C6)alkyl, wherein M+ is a suitable monovalent cation such as a sodium or lithium cation.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Compounds of the formula I and their pharmaceutically acceptable salts (hereinafter also referred to, collectively, as xe2x80x9cthe active compoundsxe2x80x9d) are useful psychotherapeutics and are potent agonists and/or antagonists of the senotonin 1A (5-HT1A) and/or serotonin 1D (5-HT1D) receptors. The active compounds are useful in the treatment of hypertension, depression, generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction (e.g., premature ejaculation), eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders).
The affinities of the compounds of this invention for the various serotonin-1 receptors can be determined using standard radioligand binding assays as described in the literature. The 5-HT1A affinity can be measured using the procedure of Hoyer et al. (Brain Res., 376, 85 (1986)). The 5-HT1D affinity can be measured using the procedure of Heuring and Peroutka (J. Neurosci., 7, 894 (1987)).
The in vitro activity of the compounds of the present invention at the 5-HT1 D binding site may be determined according to the following procedure. Bovine caudate tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS-hydrochloride (tris[hydroxymethyl]aminomethane hydrochloride) at a pH of 7.7. The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is then discarded and the resulting pellet resuspended in approximately 20 volumes of 50 mM TRIS-hydrochloride buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37xc2x0 C., after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a buffer of 15 mM TRIS-hydrochloride containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 mM pargyline and 4 mM calcium chloride (CaCl2). The suspension is kept on ice at least 30 minutes prior to use.
The inhibitor, control or vehicle is then incubated according to the following procedure. To 50 ml of a 20 percent dimethylsulfoxide (DMSO)/80 percent distilled water solution is added 200 ml of tritiated 5-hydroxytryptamine (2 nM) in a buffer of 50 mM TRIS-hydrochloride containing 0.01 percent ascorbic acid at pH 7.7 and also containing 10 mM pargyline and 4 mM calcium chloride, plus 100 nM of 8-hydroxy-DPAT (dipropylaminotetraline) and 100 nM of mesulergine. To this mixture is added 750 ml of bovine caudate tissue, and the resulting suspension is vortexed to ensure a homogenous suspension. The suspension is then incubated in a shaking water bath for 30 minutes at 25xc2x0 C. After incubation is complete, the suspension is filtered using glass fiber filters (e.g., Whatman GF/B-filters). The pellet is then washed three times with 4 ml of a buffer of 50 mM TRIS-hydrochloride at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (aquasol 2) and allowed to sit overnight. The percent inhibition can be calculated for each dose of the compound. An IC50 value can then be calculated from the percent inhibition values.
The activity of the compounds of the present invention for 5-HT1A binding ability can be determined according to the following procedure. Rat brain cortex tissue is homogenized and divided into samples of 1 gram lots and diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900 G for 10 minutes and the supernate separated and recentrifuged at 70,000 G for 15 minutes. The supernate is discarded and the pellet re-suspended in 10 volumes of 15 mM TRIS-hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37xc2x0 C. After pre-incubation is complete, the suspension is centrifuged at 70,000 G for 15 minutes and the supernate discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS-hydrochloride at pH 7.7 containing 4 mM of calcium chloride and 0.01 percent ascorbic acid. The tissue is stored at xe2x88x9270xc2x0 C. until ready for an experiment. The tissue can be thawed immediately prior to use, diluted with 10 mm pargyline and kept on ice.
The tissue is then incubated according to the following procedure. Fifty microliters of control, inhibitor, or vehicle (1 percent DMSO final concentration) is prepared at various dosages. To this solution is added 200 ml of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS-hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. To this solution is then added 750 ml of tissue and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37xc2x0 C. The solution is then filtered, washed twice with 4 ml of 10 mM TRIS-hydrochloride at pH 7.5 containing 154 mM of sodium chloride. The percent inhibition is calculated for each dose of the compound, control or vehicle. IC50 values are calculated from the percent inhibition values.
The compounds of formula I of the present invention described in the following Examples were assayed for 5-HT1A and 5-HT1D affinity using the aforementioned procedures. All such compounds of the invention that were tested exhibited IC50""s less than 0.60 mM for 5-HT1D affinity and IC50""s less than 1.0 mM for 5-HTIA affinity.
The agonist and antagonist activities of the compounds of the invention at 5-HT1A and 5-HT1D receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and 5-HT1A receptors are dissected out of the hippocampus, while 5-HT1D receptors are obtained by slicing at 350 mM on a McIlwain tissue chopper and dissecting out the substantia nigra from the appropriate slices. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a hand-held glass-Teflon(copyright) homogenizer and centrifuged at 35,000xc3x97g for 10 minutes at 4xc2x0 C. The pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of protein per tube. The following agents are added so that the reaction mix in each tube contained 2.0 mM MgCl2, 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg/mL creatine phosphokinase, 100 mM GTP and 0.5-1 microcuries of [32P]-ATP (30 Ci/mmol: NEG-003xe2x80x94New England Nuclear). Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate) at 30xc2x0 C. for 15 minutes. Each tube receives 20 mL tissue, 10 mL drug or buffer (at 10xc3x97 final concentration), 10 mL 32 nM agonist or buffer (at 10xc3x97 final concentration), 20 mL forskolin (3 mM final concentration) and 40 mL of the preceding reaction mix. Incubation is terminated by the addition of 100 mL 2% SDS, 1.3 mM CAMP, 45 mM ATP solution containing 40,000 dpm [3H]-cAMP (30 Ci/mmol: NET-275xe2x80x94New England Nuclear) to monitor the recovery of cAMP from the columns. The separation of [32P]-ATP and [32P]-cAMP is accomplished using the method of Salomon et al., Analytical Biochemistry, 1974, 58, 541-548. Radioactivity is quantified by liquid scintillation counting. Maximal inhibition is defined by 10 mM (R)-8-OH-DPAT for 5-HT1A receptors, and 320 nM 5-HT for 5-HT1D receptors. Percent inhibitions by the test compounds are then calculated in relation to the inhibitory effect of (R)-8-OH-DPAT for 5-HT1A receptors or 5-HT for 5-HT1D receptors. The reversal of agonist induced inhibition of forskolin-stimulated adenylate cyclase activity is calculated in relation to the 32 nM agonist effect.
The compounds of the invention can be tested for in vivo activity for antagonism of 5-HT1D agonist-induced hypothermia in guinea pigs according to the following procedure.
Male Hartley guinea pigs from Charles River, weighing 250-275 grams on arrival and 300-600 grams at testing, serve as subjects in the experiment. The guinea pigs are housed under standard laboratory conditions on a 7 a.m. to 7 p.m. lighting schedule for at least seven days prior to experimentation. Food and water are available ad libitum until the time of testing.
The compounds of the invention can be administered as solutions in a volume of 1 ml/kg. The vehicle used is varied depending on compound solubility. Test compounds are typically administered either sixty minutes orally (p.o.) or 0 minutes subcutaneously (s.c.) prior to a 5-HT1D agonist, such as [3-(1-methylpyrrolidin-2-ylmethylyl)-1H-indol-5-yl]-(3-nitropyridin-3-yl)-amine, which can be prepared as described in PCT publication WO93/111 06, published Jun. 10, 1993 which is administered at a dose of 5.6 mg/kg, s.c. Before a first temperature reading is taken, each guinea pig is placed in a clear plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the surroundings for 30 minutes. Animals are then returned to the same shoe box after each temperature reading. Prior to each temperature measurement each animal is firmly held with one hand for a 30-second period. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm. into the rectum and held there for 30 seconds or until a stable recording is obtained. Temperatures are then recorded.
In p.o. screening experiments, a xe2x80x9cpre-drugxe2x80x9d baseline temperature reading is made at xe2x88x9290 minutes, the test compound is given at xe2x88x9260 minutes and an additional xe2x88x9230 minute reading is taken. The 5-HT1D agonist is then administered at 0 minutes and temperatures are taken 30, 60, 120 and 240 minutes later.
In subcutaneous screening experiments, a pre-drug baseline temperature reading is made at xe2x88x9230 minutes. The test compound and 5-HT1D agonists are given concurrently and temperatures are taken at 30, 60, 120 and 240 minutes later.
Data are analyzed with two-way analysis of variants with repeated measures in Newman-Keuls post hoc analysis.
The active compounds of the invention can be evaluated as anti-migraine agents by testing the extent to which they mimic sumatriptan in contracting the dog isolated saphenous vein strip [P. P. A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1988)]. This effect can be blocked by methiothepin, a known serotonin antagonist. Sumatriptan is known to be useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. The pharmacological basis of sumatriptan efficacy has been discussed in W. Fenwick et al., Br. J. Pharmacol., 96, 83 (1989).
The serotonin 5-HT1 agonist activity can be determined by the in vitro receptor binding assays, as described for the 5-HT1A receptor using rat cortex as the receptor source and [3H]-8-OH-DPAT as the radioligand [D. Hoyer et al. Eur. J. Pharm., 118, 13 (1985)] and as described for the 5-HT1D receptor using bovine caudate as the receptor source and [3H]serotonin as the radioligand [R. E. Heuring and S. J. Peroutka, J. Neuroscience, 7, 894 (1987)]. Of the active compounds tested, all exhibited an IC50 in either assay of 1 mM or less.
The compounds of formula I may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), monoamine oxidase inhibitors (e.g. isocarboxazid, phenelzine or tranylcyclopramine) or 5-HT re-uptake inhibitors (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g, benserazide or carbidopa, or with a dopamine agonist e.g., bromocriptine, lysuride or pergolide). It is to be understood that the present invention covers the use of a compound of general formula (I) or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.
Compounds of the formula I and the pharmaceutically acceptable salts thereof, in combination with a 5-HT re-uptake inhibitor (e.g., fluvoxamine, sertraline, fluoxetine or paroxetine), preferably sertraline, or a pharmaceutically acceptable salt or polymorph thereof (the combination of a compound of formula I with a 5-HT re-uptake inhibitor is referred herein to as xe2x80x9cthe active combinationxe2x80x9d), are useful psychotherapeutics and may be used in the treatment or prevention of disorders the treatment or prevention of which is facilitated by modulating serotonergic neurotransmission such as hypertension, depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, and post partum depression), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder, panic disorder, memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g., small cell lung carcinoma), chronic paroxysmal hemicrania and headache (associated with vascular disorders).
Serotonin (5-HT) re-uptake inhibitors, preferably sertraline, exhibit positive activity against depression; chemical dependencies; anxiety disorders including panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, and post-traumatic stress disorder; obsessive-compulsive disorder; avoidant personality disorder and premature ejaculation in mammals, including humans, due in part to their ability to block the synaptosomal uptake of serotonin.
U.S. Pat. No. 4,536,518 describes the synthesis, pharmaceutical composition and use of sertraline for depression and is hereby incorporated by reference in its entirety.
Activity of the active combination as antidepressants and related pharmacological properties can be determined by methods (1)-(4) below, which are described in Koe, B. et al., Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700 (1983). Specifically, activity can be determined by studying (1) their ability to affect the efforts of mice to escape from a swim-tank (Porsolt mouse xe2x80x9cbehavior despairxe2x80x9d test), (2) their ability to potentiate 5-hydroxytryptophan-induced behavioral symptoms in mice in vivo, (3) their ability to antagonize the serotonin-depleting activity of p-chloroamphetamine hydrochloride in rat brain in vivo, and (4) their ability to block the uptake of serotonin, norepinephrine and dopamine by synaptosomal rat brain cells in vitro. The ability of the active combination to counteract reserpine hypothermia in mice in vivo can be determined according to the methods described in U.S. Pat. No. 4,029,731.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas. e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains 20 mg to 1000 mg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 mg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
In connection with the use of an active compound of this invention with a 5-HT re-uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT re-uptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.
A preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.
Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from about 0.01 mg to about 100 mg of the active compound of this invention, preferably from about 1 mg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT re-uptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.
The following Examples illustrate the preparation of the compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 47-61 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25xc2x0 C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used.